The triglyceride glucose index and cardiovascular disease outcomes
Authors: David Flood, Luisa Campos Caldeira Brant, Jeremy B Sussman
Journal: The Lancet Healthy Longevity (2022)

In The Lancet Healthy Longevity, Patricio Lopez-Jaramillo and colleagues1Lopez-Jaramillo P Gomez-Arbelaez D Martinez-Bello D et al.Association of the triglyceride glucose index as a measure of insulin resistance with mortality and cardiovascular disease in populations from five continents (PURE study): a prospective cohort study.Lancet Healthy Longev. 2022; (published online Dec 12.)https://doi.org/10.1016/S2666-7568(22)00247-1Summary Full Text Full Text PDF Scopus (7) Google Scholar present results from the Prospective Urban Rural Epidemiology (PURE) study on the association between insulin resistance and cardiovascular disease outcomes. This study1Lopez-Jaramillo P Gomez-Arbelaez D Martinez-Bello D et al.Association of the triglyceride glucose index as a measure of insulin resistance with mortality and cardiovascular disease in populations from five continents (PURE study): a prospective cohort study.Lancet Healthy Longev. 2022; (published online Dec 12.)https://doi.org/10.1016/S2666-7568(22)00247-1Summary Full Text Full Text PDF Scopus (7) Google Scholar uses PURE data to introduce a novel cardiometabolic risk factor, the triglyceride glucose (TyG) index. The TyG index is a surrogate marker for insulin resistance, often considered the key pathophysiological abnormality in diabetes and prediabetes. It is calculated as the natural log of fasting triglycerides multiplied by fasting plasma glucose and therefore is practical to measure in primary care settings with laboratory capacity. This PURE analysis included 141 243 individuals aged 35–70 years who were followed up for a median of 13·2 years (IQR 11·9–14·6) in 22 countries (5 low-income countries [LICs], 13 middle-income countries [MICs], and 4 high-income countries [HICs]). The composite primary outcome was major cardiovascular disease events (non-fatal myocardial infarction or stroke) or death due to cardiovascular diseases. In the adjusted models, individuals in the highest TyG tertile had a greater incidence of the composite outcome compared with those in the lowest TyG tertile (HR 1·21; 95% CI 1·13–1·30). Moreover, there was heterogeneity in the size of this association by country income group; a larger association was seen in LICs and MICs, while no association was observed in HICs. These findings are promising, but more knowledge is required for the role the TyG index in causal inference, describing inequity, predicting clinical risk, and implementing the marker in clinical practice. From a causal perspective, one challenge is disentangling the biological role of insulin resistance versus the known risk factors of elevated glucose and elevated triglycerides on cardiovascular disease risk.2Di Angelantonio E Sarwar N Perry P et al.Major lipids, apolipoproteins, and risk of vascular disease.JAMA. 2009; 302: 1993-2000Crossref PubMed Scopus (2069) Google Scholar, 3Sarwar N Gao P Seshasai SR et al.Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.Lancet. 2010; 375: 2215-2222Summary Full Text Full Text PDF PubMed Scopus (3312) Google Scholar In other words, how much of the explanatory power of the TyG index is not mediated via a pathway of insulin resistance? In a sensitivity analysis, the authors reported that the TyG index had a greater hazard ratio for incident cardiovascular diseases than tertiles of glucose or triglycerides in separate models. The authors hypothesise that the higher hazard ratios for the TyG index on cardiovascular diseases observed in LICs and MICs compared with HICs might be driven by differences in early life nutritional and environmental exposures, a manifestation of the double burden of malnutrition.4Wells JC Sawaya AL Wibaek R et al.The double burden of malnutrition: aetiological pathways and consequences for health.Lancet. 2020; 395: 75-88Summary Full Text Full Text PDF PubMed Scopus (341) Google Scholar Indeed, evidence from longstanding nutrition trials has emerged, supporting the adult metabolic consequences of early-life malnutrition.5Ford ND Behrman JR Hoddinott JF et al.Exposure to improved nutrition from conception to age 2 years and adult cardiometabolic disease risk: a modelling study.Lancet Glob Health. 2018; 6: e875-e884Summary Full Text Full Text PDF PubMed Scopus (47) Google Scholar As the authors note, the higher vulnerability of populations in LICs and MICs to the presence of insulin resistance in this study might also be explained by differential health-care access. Further research is needed to elucidate potential causal pathways between insulin resistance, early-life nutrition, receipt of health-care services, and cardiovascular diseases. From a descriptive perspective, the PURE study shows considerable inequities in outcomes of cardiometabolic diseases. Previous reports of the PURE study have shown a higher risk of mortality and cardiovascular disease events among individuals with diabetes who live in countries at lower levels of economic development.6Anjana RM Mohan V Rangarajan S et al.Contrasting associations between diabetes and cardiovascular mortality rates in low-, middle-, and high-income countries: cohort study data from 143,567 individuals in 21 countries in the PURE study.Diabetes Care. 2020; 43: 3094-3101Crossref PubMed Scopus (17) Google Scholar The PURE study has also provided pivotal evidence of the massive inequities in access to affordable treatment for diabetes and cardiovascular disease in LICs and MICs compared with HICs.7Chow CK Ramasundarahettige C Hu W et al.Availability and affordability of essential medicines for diabetes across high-income, middle-income, and low-income countries: a prospective epidemiological study.Lancet Diabetes Endocrinol. 2018; 6: 798-808Summary Full Text Full Text PDF PubMed Scopus (105) Google Scholar An important equity-related finding in Lopez-Jaramillo and colleagues' study is the sizeable association between the TyG index and cardiovascular disease outcomes in LICs and MICs, while there was no association in HICs. This gap is most likely due to more patients in HICs receiving risk-reducing medicines, such as blood pressure drugs and statins. Although this study was not designed as a risk prediction analysis, from a prognosis perspective, it is interesting to consider the implications of leveraging the TyG index to enhance cardiovascular disease risk prediction. A future study using PURE data might quantify the additional discriminative power gained by including the TyG index versus other commonly recommended models, such as the 2019 revised WHO cardiovascular disease risk prediction tool8The WHO CVD Risk Chart Working GroupWorld Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions.Lancet Glob Health. 2019; 7: e1332-e1345Summary Full Text Full Text PDF PubMed Scopus (470) Google Scholar or the INTERHEART Modifiable Risk Score.9McGorrian C Yusuf S Islam S et al.Estimating modifiable coronary heart disease risk in multiple regions of the world: the INTERHEART Modifiable Risk Score.Eur Heart J. 2011; 32: 581-589Crossref PubMed Scopus (181) Google Scholar Previous studies have shown modest improvements in model performance when laboratory-based measurements were added to non-laboratory models relying on inputs, such as age, sex, smoking status, blood pressure, and BMI.8The WHO CVD Risk Chart Working GroupWorld Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions.Lancet Glob Health. 2019; 7: e1332-e1345Summary Full Text Full Text PDF PubMed Scopus (470) Google Scholar, 10Joseph P Yusuf S Lee SF et al.Prognostic validation of a non-laboratory and a laboratory based cardiovascular disease risk score in multiple regions of the world.Heart. 2018; 104: 581-587Crossref PubMed Scopus (41) Google Scholar Finally, from an implementation perspective, the authors conclude that the TyG index is suitable for use in routine clinical practice. We see two important challenges that need to be addressed: first, to show that the diagnosis of insulin resistance via the TyG index would meaningfully change clinical decision making, and second, to build on ongoing efforts to improve access to laboratory measurements in primary care settings in many LICs and MICs.11Fleming KA Horton S Wilson ML et al.The Lancet Commission on diagnostics: transforming access to diagnostics.Lancet. 2021; 398: 1997-2050Summary Full Text Full Text PDF PubMed Scopus (84) Google Scholar Research exploring novel risk-prediction variables in diverse global populations is important. At the same time, the PURE collaborators most likely would agree that the top priority is to improve the low implementation of evidence-based cardiovascular disease care in LICs and MICs, and among marginalised populations in HICs. In summary, this study shows the association of a simple surrogate measure of insulin resistance, the TyG index, with cardiovascular disease outcomes, and how this association differs by countries' level of economic development. The study marks a valuable step in a long path to clinical use. Future causal, descriptive, prognostic, and implementation research will help to better understand how insulin resistance influences cardiometabolic outcomes worldwide. DF is supported by a grant (award number K23HL161271) from the US National Heart, Lung, And Blood Institute of the National Institutes of Health. LCCB and JBS declare no competing interests. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Association of the triglyceride glucose index as a measure of insulin resistance with mortality and cardiovascular disease in populations from five continents (PURE study): a prospective cohort studyThe TyG index is significantly associated with future cardiovascular mortality, myocardial infarction, stroke, and type 2 diabetes, suggesting that insulin resistance plays a promoting role in the pathogenesis of cardiovascular and metabolic diseases. Potentially, the association between the TyG index and the higher risk of cardiovascular diseases and type 2 diabetes in LICs and MICs might be explained by an increased vulnerability of these populations to the presence of insulin resistance. Full-Text PDF Open Access